Cellular therapy: exploiting NK cell alloreactivity in transplantation

Allogeneic hematopoietic transplantation relies on T-cell alloreactions for engraftment and the graft-versus-leukemia (GVL) effect. In human leukocyte antigen (HLA) haplotype-mismatched transplants, extensive T-cell depletion of the graft is essential to prevent GVHD. This raises the question of whe ther mismatched transplants exert any GVL effect and whether it will ever b e possible to reduce the intensity of preparative regimens. Because natural killer (NK) cells are negatively regulated by MHC class I-specific inhibit ory receptors, mismatched transplants may trigger NK-cell alloreactivity. H LA class I disparities driving NK-cell alloreactions in the GVH direction m ediate strong GVL effects, produce higher engraftment rates, and do not cau se GVHD. In murine MHC-mismatched transplant models with no donor T-cell re activity against the recipient, the pre-transplant infusion of donor-vs-rec ipient alloreactive INK cells conditioned the recipients to bone marrow tra nsplantation without GVHD. NK-cell alloreactivity may be a unique therapeut ic tool for tolerance induction and clearance of leukemia in hematopoietic transplantation. (C) 2001 Lippincott Williams & Wilkins, Inc.